Adsorbent for the removal of blood cells

ABSTRACT

An adsorbent for the removal of blood cells, which is formed from a hydrophobic polymer resin and has a surface center line average roughness of 5 to 100 nm. The hydrophobic polymer resin is preferably a polyarylate resin (PAR), polyethersulfone resin (PES), polysulfone resin (PSF), or a polymer alloy consisting of two or more of these resins. The adsorbent for the removal of blood cells can take the form of beads, hollow fibers, or solid fibers.

TECHNICAL FIELD

The present invention relates to an adsorbent for the removal of bloodcells, which is used for removing the white blood cells and bloodplatelets contained within blood.

BACKGROUND ART

In recent years, white blood cell adsorption devices have started to beused widely as treatment devices for inflammatory bowel disease (IBD)and rheumatoid arthritis (RA). White blood cell adsorption devices usethe principles of adsorption and filtration to directly remove the whiteblood cells, which can cause inflammation, from the blood, and have beenshown to have a therapeutic effect. The main advantage of medicaltreatments using a white blood cells adsorption device is that, unliketreatments using drugs, side-effects are minimal. For the white bloodcell adsorption devices in current use, methods that employ a carrierhaving a specified surface roughness and methods that employ a filtercomposed of ultra-fine polymer fibers have been proposed.

For example, Patent Document 1 discloses a carrier for adsorbinggranulocytes that has an irregular surface for which the center lineaverage roughness Ra is within a range from 0.2 μm to 100 μm and theaverage spacing Sm between irregularities is within a range from 5 μm to200 μm.

Further, Patent Document 2 proposes a method of producing porous beadsin which at least two polymers each having a number average molecularweight of at least 10,000 but having different coagulation values aredissolved in a solvent that exhibits favorable compatibility with eachpolymer, and the resulting polymer solution is then added dropwise to acoagulant containing a non-solvent, thereby causing coagulation andproducing porous beads.

Moreover, Patent Document 3 discloses a technique in which by aligningthe fibers of an organic polymer with a high degree of regularity,namely in a substantially parallel arrangement, and then passing bloodbetween these fibers, the white blood cells can be captured on thesurface of the fibers while those problems that have proven difficult toprevent using filters formed from nonwoven fabrics or the like, such asthe destruction of blood cells and the coagulation of the blood, can beovercome.

These methods have been proposed for removing mainly the white bloodcells such as granulocytes and lymphocytes from the blood of patientssuffering from cancer or immune system abnormalities. However, recentresearch has made it clear that particularly in the case of inflammatorydiseases such as autoimmune disease, it is not only the white bloodcells, but also the platelets within the blood, that act as inflammatorycells.

PRIOR ART

Patent Document

PATENT DOCUMENT 1: JP 05-168706 A

PATENT DOCUMENT 2: JP 62-243561 A

PATENT DOCUMENT 3: EP 1,931,404

DISCLOSURE OF INVENTION

Problems to be Solved by the Invention

The present invention proposes an adsorbent for the removal of bloodcells that suffers minimal problems such as in-circuit coagulationduring blood flow, and enables efficient removal of white blood cellsand platelets.

Means for Solving the Problems

One aspect of the present invention relates to an adsorbent for removingblood cells. The adsorbent for removing blood cells is formed from ahydrophobic polymer resin, and has a surface center line averageroughness (Ra) of 5 to 100 nm.

By using the adsorbent for removing blood cells of this aspect, whiteblood cells and platelets can be removed efficiently from the blood,while the occurrence of blood coagulation during passage of the bloodthrough a column or circuit is suppressed.

In the aspect described above, the hydrophobic polymer resin may be apolyarylate resin having a repeating unit represented by chemicalformula (1) shown below.

In chemical formula (1), each of R1 and R2 represents a lower alkylgroup of 1 to 5 carbon atoms, and R1 and R2 may be the same ordifferent.

In the aspect described above, the hydrophobic polymer resin may be apolyethersulfone resin having a repeating unit represented by chemicalformula (2) or chemical formula (3) shown below.

In chemical formula (2), each of R3 and R4 represents a lower alkylgroup of 1 to 5 carbon atoms, and R3 and R4 may be the same ordifferent.

In the aspect described above, the hydrophobic polymer resin may includea polyarylate resin having a repeating unit represented by chemicalformula (1) shown above, and a polyethersulfone resin having a repeatingunit represented by chemical formula (2) or chemical formula (3) shownabove.

The adsorbent for removing blood cells according to the aspect describedabove may be in the form of beads. Further, the adsorbent for removingblood cells according to the aspect described above may also exist inthe form of hollow thread-like fibers or solid thread-like fibers.Furthermore, the adsorbent for removing blood cells according to theaspect described above may be used for the removal of white blood cellsand platelets from blood.

Appropriate combinations of each of the elements described above arealso deemed to be included within the scope of the invention for whichpatent protection is sought on the basis of the present description.

ADVANTAGES OF THE INVENTION

According to the present invention, white blood cells and platelets canbe removed efficiently from blood with minimal problems such asin-circuit coagulation during blood flow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a porous beads productionapparatus used in the production of beads for removing blood cells.

FIG. 2 is an exploded perspective view illustrating a general outline ofa blood cells removal module using beads for removing blood cellsaccording to example 1.

FIG. 3 is an AFM image (10 μm×10 μm) of beads for removing blood cellsaccording to example 3.

FIG. 4 is an AFM image (10 μm×10 μm) of beads for removing blood cellsaccording to comparative example 3.

FIG. 5 is an exploded perspective view illustrating a general outline ofa blood cells removal module using hollow fibers according to example 4.

FIG. 6A is a perspective view of the structure of a blood cells removalmodule according to an embodiment.

FIG. 6B is an exploded perspective view of the structure of a bloodcells removal module according to an embodiment.

FIG. 7 is a perspective view of one example of the structure of a bloodcells removal module according to an embodiment of the presentinvention.

FIG. 8 is an exploded perspective view of one example of a blood cellsremoval module according to an embodiment of the present invention.

FIG. 9 is a diagram describing one example of a method of producing ablood cells removal module according to an embodiment of the presentinvention.

FIG. 10 is a diagram describing the structure of a cylindrical adsorbentfor removing blood cells according to an embodiment of the presentinvention, and illustrates one example of the cross-section along theline A-A in FIG. 8.

FIG. 11 is a diagram describing the structure of a cylindrical adsorbentfor removing blood cells according to an embodiment of the presentinvention, and illustrates another example of the cross-section alongthe line A-A in FIG. 8.

BEST MODE FOR CARRYING OUT THE INVENTION

[First Embodiment]

An adsorbent for removing blood cells according to this embodiment isformed from a hydrophobic polymer resin, and has a surface center lineaverage roughness (Ra) of 5 to 100 nm.

By ensuring that the material at the surface of the adsorbent is ahydrophobic polymer resin, the resulting hydrophobic interactions areable to improve the adsorption of white blood cells such as granulocytesand lymphocytes, and platelets.

The hydrophobic polymer resin is preferably a polyarylate resin (PAR),polyethersulfone resin (PBS), polysulfone resin (PSF), or a polymeralloy of these resins.

A polyarylate resin is a resin having a repeating unit represented bychemical formula (1) shown below. The number average molecular weight ofthe polyarylate resin is preferably within a range from 20,000 to30,000. If the number average molecular weight of the polyarylate resinexceeds 30,000, then the surface roughness tends to become too great,and forming an appropriate level of surface roughness becomes difficult.In contrast, if the number average molecular weight of the polyarylateresin is less than 20,000, then the strength of the adsorbent forremoving blood cells tends to deteriorate, and the production yield ofthe adsorbent for removing blood cells worsens.

In chemical formula (1), each of R1 and R2 represents a lower alkylgroup of 1 to 5 carbon atoms, and R1 and R2 may be the same ordifferent. Specific examples of R1 and R2 include a methyl group, ethylgroup, propyl group, butyl group and pentyl group. R1 and R2 arepreferably methyl groups.

There are no particular limitations on the polyarylate resin, providedthat the repeating unit represented by chemical formula (1) representsthe main repeating unit, and the polyarylate resin may also includeother repeating units, provided they do not impair the effects of thepresent invention.

A polyethersulfone resin is a resin having a repeating unit representedby chemical formula (2) or chemical formula (3) shown below. The numberaverage molecular weight of the polyethersulfone resin is preferablywithin a range from 15,000 to 30,000. If the number average molecularweight of the polyethersulfone resin exceeds 30,000, then the surfaceroughness tends to become too great, and forming an appropriate level ofsurface roughness becomes difficult. In contrast, if the number averagemolecular weight of the polyethersulfone resin is less than 15,000, thenthe strength of the adsorbent for removing blood cells tends todeteriorate, and the production yield of the adsorbent for removingblood cells worsens.

In chemical formula (2), each of R3 and R4 represents a lower alkylgroup of 1 to 5 carbon atoms, and R3 and R4 may be the same ordifferent. Specific examples of R3 and R4 include a methyl group, ethylgroup, propyl group, butyl group and pentyl group. R3 and R4 arepreferably methyl groups.

Ensuring that the surface Ra value of the adsorbent for removing bloodcells is within a range from 5 to 100 nm enables a further improvementin the adsorption of white blood cells and platelets. Achieving asurface Ra value of less than 5 nm for the adsorbent for removing bloodcells is problematic from a production perspective. In contrast, if thesurface Ra value of the adsorbent for removing blood cells exceeds 100nm, then the contribution of the adsorbent to the adsorption ofplatelets (size: 2 to 4 μm) tends to decrease, and production of theadsorbent by a coagulation method becomes problematic. The surface Ravalue of the adsorbent for removing blood cells can be measured using anAFM (atomic force microscope). The AFM measurement region is typically10 μm×10 μm.

The adsorbent for removing blood cells according to this embodiment isideal for use within a treatment for removing white blood cells andplatelets. Specifically, by packing the adsorbent for removing bloodcells according to the embodiment inside a column, and then passingblood through the column, white blood cells and platelets can be removedfrom the blood. In this case, by packing the adsorbent for removingblood cells inside the column, passages are formed between adjacentparticles of the adsorbent for removing blood cells, thereby ensuring aready flow of blood and suppressing the occurrence of blood coagulation.Moreover, the white blood cells and platelets can be removed simply andefficiently from the blood without requiring the use of a complexapparatus.

The adsorbent for removing blood cells preferably exists in the form ofbeads or fibers such as hollow thread-like fibers or solid thread-likefibers.

In those cases where the adsorbent for removing blood cells exists inthe form of beads (hereafter referred to as “beads for removing bloodcells”), the diameter of the beads is preferably within a range from 0.5to 5 mm. Forming the adsorbent for removing blood cells as beads yieldsthe effects described below.

-   (1) Compared with LCAP (leukocytapheresis) using an ultra-fine    fibrous nonwoven fabric, pressure loss within the column is minimal    and problems such as coagulation are relatively minor, even in those    cases where the viscosity of the blood from the patient is high, and    there is a high risk of problems such as coagulation within the    column.-   (2) Unlike LCAP, lymphocytes are not removed, meaning the danger of    removing immunity-related memory cells is reduced.-   (3) Compared with GCAP (granulocytapheresis), which also uses a    beads-type adsorbent, a larger amount of platelets can be removed,    and therefore inflammation symptoms derived from platelets can be    more effectively suppressed.-   (4) Because treatment can be performed simply by passing the whole    blood through a disposable column, a treatment can be provided that    offers simplicity and a high level of safety.-   (5) Because expensive equipment such as a centrifuge is not    required, the treatment can be performed inexpensively.

Furthermore, in those cases where the adsorbent for removing blood cellsexists in the form of hollow fibers or solid fibers (hereafter referredto as “hollow fibers for removing blood cells” and “solid fibers forremoving blood cells” respectively), the fibers preferably have anexternal diameter of 0.1 to 5 mm. Forming the adsorbent for removingblood cells as hollow fibers or solid fibers yields the effectsdescribed below besides the effects listed above.

-   (1) Compared with LCAP using an ultra-fine fibrous nonwoven fabric,    forming the adsorbent for removing blood cells as hollow fibers or    solid fibers enables treatment to be performed with comparatively    few problems, even in those cases where the viscosity of the blood    from the patient is high, and there is a high risk of problems such    as coagulation within the column.-   (2) By using hollow fibers or solid fibers, the production    efficiency of the adsorbent for removing blood cells can be    improved, thereby reducing the production costs.    [Method of Producing Beads for Removing Blood Cells]

A method of producing beads for removing blood cells according to anembodiment of the present invention is described below. First, thehydrophobic polymer resin is dissolved in N-methyl-2-pyrrolidone(hereafter referred to as NMP) to prepare a polymer solution (the stocksolution). A mixture prepared by mixing NMP with water is used as thecoagulant. The polymer solution is added dropwise to the coagulant bathfrom a nozzle having an internal diameter of 0.25 mm and from a heightapproximately 10 cm above the liquid surface within the tank (see FIG.1). Following thorough coagulation within the coagulant, the resultingbeads are washed with distilled water to obtain the beads for removingblood cells.

FIG. 1 is a schematic illustration of a blood cells removal beadsproduction apparatus 100 used in the production of beads for removingblood cells. The stock solution stored in a stock solution tank 110 issupplied to a nozzle 130 using a pump 120. The stock solution suppliedto the nozzle 130 drips down from the nozzle 130. A coagulant bath 140containing the coagulant is provided beneath the nozzle 130. Thecoagulant bath 140 may also be provided with a rotor (not shown in thefigure) for generating a spiral-like flow within the coagulant.

An overflow pipe 142 is fitted to the upper portion of the coagulantbath 140. When the liquid level of the coagulant contained within thecoagulant bath 140 reaches the port where the overflow pipe 142 isattached, the overflowing coagulant flows down through the overflow pipe142 and is collected in a coagulant collection tank 144. A mesh 143having a mesh size that is finer than the diameter of the beads 150 forremoving blood cells produced within the coagulant bath 140 ispreferably provided at the port where the overflow pipe 142 is attached.This prevents beads 150 for removing blood cells from contaminating thecoagulant collection tank 144 as foreign matter.

The coagulant collected in the coagulant collection tank 144 is pumpedback up using a coagulant circulation pump 146 and returned to thecoagulant bath 140. The amount of the coagulant supplied from thecoagulant collection tank 144 to the coagulant bath 140 is detected by aflow rate meter 147, and an appropriate amount of the coagulant issupplied to the coagulant bath 140 using a coagulant supply volumeregulating valve 148. By circulating the overflowed coagulant in thismanner, the coagulant can be used more efficiently, and the productioncosts for the beads 150 for removing blood cells can be kept to aminimum.

The stock solution that is dripped into the coagulant bath 140 from thenozzle 130 solidifies in a spherical form within the coagulant, thusforming the beads 150 for removing blood cells. By adding the stocksolution dropwise to the coagulant, the spherical beads 150 for removingblood cells can be obtained in a stable manner with good yield.

The solidified beads 150 for removing blood cells are discharged fromthe bottom of the coagulant bath 140, and collected on a screen 160having a mesh size that is finer than the diameter of the beads 150 forremoving blood cells. The volume of the coagulant containing the beads150 for removing blood cells discharged from the coagulant bath 140 isregulated appropriately using a coagulant discharge volume regulatingvalve 170. The coagulant discharged from the coagulant bath 140 togetherwith the beads 150 for removing blood cells is collected in thecoagulant collection tank 144 and reused.

[Method of Producing Hollow Fibers for Removing Blood Cells]

A method of producing hollow fibers for removing blood cells accordingto an embodiment of the present invention is described below. First, thehydrophobic polymer resin is dissolved in an organic solvent to preparea spinning stock solution. There are no particular limitations on theorganic solvent, provided it acts as a good solvent with respect to thehydrophobic polymer resin, and specific examples includetetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide and NMP.Of these, NMP is preferred as the organic solvent.

By using a double nozzle to extrude the spinning stock solution togetherwith an internal coagulant (an organic solvent containing water) anddropping the solution into an external coagulant (an organic solventcontaining water), hollow fibers for removing blood cells can beproduced. The temperature during spinning of these hollow fibers forremoving blood cells is preferably within a range from approximately 5to 15° C. By setting the spinning temperature within this range, thestability of the spinning stock solution is improved, thereby inhibitingphase separation and the like. The ratio between the concentrations ofthe internal coagulant (the core liquid) and the external coagulant ispreferably within a range from 0.6 to 1.6.

[Method of Producing Solid Fibers for Removing Blood Cells]

A method of producing solid fibers for removing blood cells according toan embodiment of the present invention is described below. First, thehydrophobic polymer resin is dissolved in an organic solvent to preparea spinning stock solution. There are no particular limitations on theorganic solvent, provided it acts as a good solvent with respect to thehydrophobic polymer resin, and specific examples includetetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide and NMP.Of these, NMP is preferred as the organic solvent.

By using a typical nozzle (orifice) to drop the spinning stock solutioninto a coagulant (an organic solvent containing water), solid fibers forremoving blood cells can be produced. The temperature during spinning ofthese solid fibers for removing blood cells is preferably within a rangefrom approximately 5 to 15° C. By setting the spinning temperaturewithin this range, the stability of the spinning stock solution isimproved, thereby inhibiting phase separation and the like.

[Second Embodiment]

An embodiment of the present invention is described below with referenceto the drawings. FIG. 6A is a perspective view of the structure of ablood cells removal module according to the embodiment. FIG. 6B is anexploded perspective view of the structure of the blood cells removalmodule according to the embodiment. The blood cells removal module 10comprises a casing 20 and an adsorbent 50 for removing blood cells.

The casing 20 comprises a casing main body 21, a pair of meshes 30 a and30 b, and a pair of headers 40 a and 40 b. The casing main body 21 is acircular cylindrical member produced from a polycarbonate. However, thematerial for the casing main body 21 is not limited to polycarbonate,and other known resin materials, metal materials or composite materialsmay also be used.

The pair of polyester meshes 30 a and 30 b are attached to the two openends of the casing main body 21. These meshes 30 a and 30 b have a meshsize that is finer than the external diameter of the adsorbent 50 forremoving blood cells described below, meaning the meshes retain theadsorbent 50 for removing blood cells inside the casing. The materialfor the meshes 30 a and 30 b is not limited to polyester, and otherknown resin materials, metal materials or composite materials may alsobe used.

A header 40 a is fitted to one of the open ends of the casing main body21 with the aforementioned mesh 30 a sandwiched therebetween. An inlet22 that functions as the blood introduction point is provided in theheader 40 a. Further, a header 40 b is fitted to the other open end ofthe casing main body 21 with the aforementioned mesh 30 b sandwichedtherebetween. An outlet 24 that functions as the blood discharge pointis provided in the header 40 b. The two open ends of the casing mainbody 21 are sealed by the header 40 a and the header 40 b. In order toachieve more reliable sealing, sealing members such as O-rings may beprovided between the header 40 a and the casing main body 21 and betweenthe header 40 b and the casing main body 21.

The inside of the casing main body 21 between the pair of meshes 30 aand 30 b houses the adsorbent 50 for removing blood cells. The adsorbent50 for removing blood cells is arranged randomly inside the casing mainbody 21, namely in an irregular and unrestrained manner. The adsorbent50 for removing blood cells is composed of short hollow fibers or shortsolid fibers, wherein the length of the fibers is preferably within arange from 1 to 60%, and more preferably 18 to 56%, of the internaldiameter of the casing main body 21. Setting the length of the adsorbent50 for removing blood cells to a value of less than 1% of the internaldiameter of the casing main body 21 tends to cause a deterioration inproductivity. In contrast, if the length of the adsorbent 50 forremoving blood cells exceeds 60% of the internal diameter of the casingmain body 21, then the fibers of the adsorbent 50 for removing bloodcells tend to interfere with each other inside the casing main body 21,thereby restricting free movement of the individual fibers of theadsorbent 50 for removing blood cells, and if air becomes trapped by afiber, then removal of that air from the casing becomes difficult. Inother words, because air removal becomes more difficult, the residualair is more likely to cause coagulation within the blood. Further, thecontact surface area between the adsorbent for removing blood cells andthe blood decreases, which may result in a reduction in the adsorptionperformance.

The filling rate of the adsorbent 50 for removing blood cells relativeto the volume of the casing main body 21 is preferably within a rangefrom 20 to 60%. Ensuring that the filling rate of the adsorbent 50 forremoving blood cells is at least 20% reduces the blood volume requiredfor blood purification, thereby lightening the impact on the patient. Incontrast, if the filling rate of the adsorbent 50 for removing bloodcells exceeds 60%, then the filling process becomes difficult, and maycause a reduction in the operating efficiency.

The adsorbent 50 for removing blood cells is formed from a hydrophobicpolymer resin. Consequently, the surface of the adsorbent 50 forremoving blood cells is hydrophobic, and the resulting hydrophobicinteractions are able to efficiently remove not only the granulocytesthat function as inflammatory cells, but also the platelets. Moreover,inflammatory symptoms caused by autoimmune disease can be suppressedwith minimal side-effects.

The same resins as those described above for the first embodiment may beused as the hydrophobic polymer resin. Accordingly, description of theresin is omitted here.

Ensuring that the surface Ra value of the adsorbent for removing bloodcells is within a range from 5 to 100 nm enables a further improvementin the adsorption of white blood cells and platelets. As mentionedabove, achieving a surface Ra value of less than 5 nm for the adsorbentfor removing blood cells is problematic from a production perspective.In contrast, if the surface Ra value of the adsorbent for removing bloodcells exceeds 100 nm, then the contribution of the adsorbent to theadsorption of platelets (size: 2 to 4 μm) tends to decrease. The surfaceRa value of the adsorbent for removing blood cells can be measured usingan AFM (atomic force microscope). The AFM measurement region istypically 10 μm×10 μm.

By employing the blood cells removal module described above, stimulationof the coagulation system is minimal, so that when the module is used asa blood purification column during a medical treatment, coagulation ofthe blood during the treatment is unlikely. Further, air removal duringpriming (blood introduction) can be performed favorably.

Furthermore, because the adsorbent for removing blood cells can beproduced with a high degree of production efficiency simply by cutting ahollow or solid fiber that is able to be produced in a continuousmanner, the cost of the blood cells removal module can be reduced.

[Third Embodiment]

A blood cells removal module and a method of producing the blood cellsremoval module according to another embodiment of the present inventionare described below. Those structural members that are the same as thosedescribed above in the first and second embodiments are referred tousing the same labels, and the description of these members is omitted.

As illustrated in FIG. 7 and FIG. 8, the blood cells removal module 300according to this embodiment has a cylindrical adsorbent 350 forremoving blood cells contained inside a casing 20. The casing 20comprises a casing main body 21, a pair of headers 40 a and 40 b fittedwith a blood inlet 22 and blood outlet 24 respectively, and wherenecessary a pair of meshes 30 a and 30 b.

As illustrated in FIG. 8, FIG. 9 and FIG. 10, the cylindrical adsorbent350 for removing blood cells is formed by rolling an integrated bloodcells removal adsorbent-containing mesh-like fabric 60, in which anadsorbent 54 for removing blood cells that is formed from a plurality ofaligned hollow fibers or solid fibers is secured at both ends to amesh-like fabric 52 that is permeable to blood, along the direction ofalignment of the adsorbent 54 for removing blood cells. When securingboth ends of the adsorbent 54 for removing blood cells to the mesh-likefabric 52 that is permeable to blood, an adhesive may be used to securethe two members, or both ends of the adsorbent 54 for removing bloodcells may be secured by fusing the ends to the mesh-like fabric 52 thatis permeable to blood. In those cases where the adsorbent 54 forremoving blood cells is composed of hollow fibers, using fusion (andparticularly thermal fusion) to secure the fibers enables the hollows atboth ends of the adsorbent for removing blood cells to be sealed moreeasily than a securing process that uses an adhesive. As a result, whenincorporated within the blood cells removal module 300, penetration ofblood components into the interior of the hollow fibers can besuppressed, thereby preventing blood retention within the fibers.

A method of producing the cylindrical adsorbent 350 for removing bloodcells and the blood cells removal module according to this embodiment isdescribed with reference to FIG. 9. This description focuses on anexample where fusion is used as the method of securing both ends of theadsorbent 54 for removing blood cells to the mesh-like fabric 52 that ispermeable to blood. As illustrated in FIG. 9, the adsorbent 54 forremoving blood cells that is formed from a plurality of aligned hollowfibers or solid fibers is first arranged on top of the mesh-like fabric52, which is formed from a mesh or the like and is permeable to blood.Next, a fusion device 70 is used to fuse and secure both ends of theadsorbent 54 for removing blood cells to the mesh-like fabric 52,thereby sealing the ends of the adsorbent 54 for removing blood cells(S100) and forming the integrated blood cells removaladsorbent-containing mesh-like fabric 60. This fusion device 70 may useeither thermal fusion or ultrasonic fusion. As described below, theadsorbent 54 for removing blood cells is formed from a resin, and themesh-like fabric 52 is also formed from a resin. Accordingly, by usingthe fusion device 70, both ends of the adsorbent 54 for removing bloodcells can be secured to the mesh-like fabric 52 without using anadhesive, and both ends of the adsorbent 54 for removing blood cells canbe sealed. The end portions outside the fused portions 56 of theintegrated blood cells removal adsorbent-containing mesh-like fabric 60may be either left or cut off and removed. Subsequently, the obtainedintegrated blood cells removal adsorbent-containing mesh-like fabric 60is rolled along the direction of alignment of the adsorbent 54 forremoving blood cells, as indicated by the white arrow in the figure(S110), thus forming the cylindrical adsorbent 350 for removing bloodcells, which is composed of a bundle of the fibers of the adsorbent 54for removing blood cells with the mesh-like fabric 52 interposedtherebetween as a spacer (S112). The blood cells removal moduleaccording to the present embodiment is then produced by housing thecylindrical adsorbent 350 for removing blood cells inside the casing 20.Instead of employing the fusion securing method described above, anadhesive may be used for the securing process, with the ends of theadsorbent 54 for removing blood cells then sealed with an adhesive ifrequired.

In the produced cylindrical adsorbent 350 for removing blood cells, themesh-like fabric 52 functions as a spacer for the adsorbent 54 forremoving blood cells formed from the plurality of hollow fibers or solidfibers, and as a result, the distance between individual fibers of theadsorbent 54 for removing blood cells housed inside the casing 20 issubstantially uniform throughout the blood cells removal module, andthis distance is formed with an appropriate spacing. Accordingly,stagnation of the blood flow through the blood cells removal module issuppressed, the blood cells adsorption efficiency of the blood cellsremoval module of the present embodiment improves, and because unlikeconventional modules, the ends of the adsorbent for removing blood cellscomposed of fibers need not necessarily be secured using a mesh, thenumber of components in the module can be reduced and the productionprocess can be simplified.

Furthermore, in those cases where the adsorbent 54 for removing bloodcells is composed of hollow fibers, because the hollows at both endfaces of the thermally fused adsorbent 54 for removing blood cells aresealed, penetration of the blood into the interior of the hollow fibersof the adsorbent 54 for removing blood cells during blood cells removal,resulting in blood retention, can be suppressed.

The cylindrical adsorbent 350 for removing blood cells according to thisembodiment may be formed by arranging either one layer or a plurality oflayers of the adsorbent 54 for removing blood cells on top of themesh-like fabric 52, fusing both ends of the adsorbent 54 for removingblood cells, and then rolling the fabric. Examples of the structure ofthe cylindrical adsorbent 350 for removing blood cells according to thisembodiment are described below, using the cross-sectional views alongthe line A-A in FIG. 8 illustrated in FIG. 10 and FIG. 11. FIG. 10illustrates a cylindrical adsorbent 350 for removing blood cells that isformed by aligning and then fusing one layer of the adsorbent 54 forremoving blood cells on top of the mesh-like fabric 52, and then rollingthe fabric along the direction of alignment of the adsorbent 54 forremoving blood cells. Further, FIG. 11 illustrates a cylindricaladsorbent 350 a for removing blood cells that is formed by aligning andthen fusing two layers of the adsorbent 54 for removing blood cells ontop of the mesh-like fabric 52, and then rolling the fabric along thedirection of alignment of the adsorbent 54 for removing blood cells. Adecision as to how many layers of the adsorbent 54 for removing bloodcells should be aligned and then fused on top of the mesh-like fabric 52can be made on the basis of factors such as the diameter and length ofthe fibers of the adsorbent 54 for removing blood cells, and theviscosity of the blood to be passed through the adsorbent.

Next is a description of specifics relating to the adsorbent 54 forremoving blood cells formed from hollow fibers or solid fibers that isused in the blood cells removal module according to the presentembodiment. The adsorbent 54 for removing blood cells is formed from ahydrophobic polymer resin. Consequently, the surface of the adsorbent 54for removing blood cells is hydrophobic, and the resulting hydrophobicinteractions are able to efficiently remove not only the granulocytesthat function as inflammatory cells, but also the platelets. Moreover,inflammatory symptoms caused by autoimmune disease can be suppressedwith minimal side-effects.

The same resins as those described above for the first embodiment may beused as the hydrophobic polymer resin. Accordingly, description of theresin is omitted here.

Ensuring that the surface Ra value of the adsorbent for removing bloodcells is within a range from 5 to 100 nm enables a further improvementin the adsorption of white blood cells and platelets. As mentionedabove, achieving a surface Ra value of less than 5 nm for the adsorbentfor removing blood cells is problematic from a production perspective.In contrast, if the surface Ra value of the adsorbent for removing bloodcells exceeds 100 nm, then the contribution of the adsorbent to theadsorption of platelets (size: 2 to 4 μm) tends to decrease. The surfaceRa value of the adsorbent for removing blood cells can be measured usingan AFM (atomic force microscope). In this embodiment, measurement of thesurface Ra value of the adsorbent for removing blood cells is performedusing an “SPA400” apparatus manufactured by Seiko Instruments, Inc. asthe AFM and a “DFM SZDF20AL” (manufactured by Seiko Instruments, Inc.)as the probe, with the AFM measurement set to 10 μm×10 μm.

The adsorbent for removing blood cells formed from fibers according tothe present embodiment is produced by a coagulation method comprisingeither the method of producing a hollow fiber-based adsorbent forremoving blood cells described above or the method of producing a solidfiber-based adsorbent for removing blood cells described above.

Furthermore, the adsorbent for removing blood cells formed from fibersaccording to the present embodiment is composed of hollow fibers orsolid fibers with an external diameter of 0.1 mm to 5 mm, and theaverage pore diameter on the surface of the adsorbent for removing bloodcells formed from fibers of the present embodiment is within a rangefrom 50 nm to 300 nm.

Because the fibers of the adsorbent for removing blood cells accordingto this embodiment are straight fibers, the adsorbent can be used morereadily than adsorbents that employ an ultra-fine fibrous nonwovenfabric (such as the product “Cellsorba” manufactured by Asahi KaseiCorporation), even in those cases where the viscosity of the blood fromthe patient is high, and there is a high risk of problems such ascoagulation within the blood cells removal module.

The mesh-like fabric used in the present embodiment is preferablycomposed of a mesh in which the fiber diameter (strand diameter) iswithin a range from 20 μm to 100 μm, and the number of strands of fiberper inch is within a range from 3 to 80 (3 to 80 mesh), and the materialfor the mesh may be selected from polyester, nylon, polyethylene andpolypropylene.

Unlike LCAP (leukocytapheresis), the blood cells removal moduleaccording to this embodiment does not remove lymphocytes, meaning thedanger of removing immunity-related memory cells is low. Further, asdescribed below, the cylindrical adsorbent for removing blood cells thatis used in the blood cells removal module according to this embodimentis capable of removing more platelets than an adsorbent “Adacolumn”(manufactured by JIMRO Co., Ltd.) formed from cellulose acetate beadsthat is used in GCAP (granulocytapheresis). As a result, inflammatorysymptoms within a patient can be efficiently suppressed. Furthermore,with the blood cells removal module according to this embodiment,treatment can be performed simply by passing the whole blood through themodule, and therefore the treatment is simple and safe, and does notrequire the expensive equipment such as a centrifuge that is used inconventional centrifuge methods.

EXAMPLES Example 1

A polyarylate resin (hereafter abbreviated as “PAR”, number averagemolecular weight: 25,000) was dissolved in NMP to prepare a polymersolution. The weight mixing ratio between the PAR and the NMP was set to15.0:85.0. A mixture containing 60% of NMP in water was prepared as acoagulant. The polymer solution was added dropwise to the coagulant bathfrom a nozzle having an internal diameter of 0.25 mm and from a heightapproximately 10 cm above the liquid surface within the tank. Followingthorough coagulation within the coagulant, the resulting beads werewashed with distilled water, yielding beads for removing blood cellswith a diameter of approximately 1.5 mm. These beads for removing bloodcells of example 1 were substantially spherical, and the proportion(yield) of the beads having a shape that was usable as an adsorbent was99.6% (calculated for 1,000 beads).

Subsequently, as illustrated in FIG. 2, the obtained beads 190 forremoving blood cells were packed inside a circular cylindrical casing210 produced from a polycarbonate, and with a pair of polyester meshes220 positioned to prevent the beads 190 for removing blood cells fromleaking out of the casing, headers 230 fitted with a blood inlet portand a blood outlet port respectively were attached to the casing tocomplete the module. The meshes 220 used had a mesh size that was finerthan the diameter of the beads 190 for removing blood cells.

AFM measurements (10 μm×10 μm, SPA400 apparatus manufactured by SeikoInstruments, Inc., probe: DFM SZDF20AL manufactured by SeikoInstruments, Inc.) confirmed that the surface Ra value for the beads forremoving blood cells of example 1 was 15 nm.

Example 2

A polyethersulfone resin (hereafter abbreviated as “PES”, grade: 4800P,number average molecular weight: 21,000) was dissolved inN-methyl-2-pyrrolidone (hereafter abbreviated as NMP) to prepare apolymer solution. The weight mixing ratio between the PES and the NMPwas set to 15.0:85.0. A mixture containing 36% of NMP in water wasprepared as a coagulant. The polymer solution was added dropwise to thecoagulant bath from a nozzle having an internal diameter of 0.25 mm andfrom a height approximately 10 cm above the liquid surface within thetank. Following thorough coagulation within the coagulant, the resultingbeads were washed with distilled water, yielding beads for removingblood cells with a diameter of approximately 1.5 mm. These beads forremoving blood cells of example 2 were substantially spherical, and theproportion of the beads having a shape that was usable as an adsorbentwas 99.8% (calculated for 1,000 beads). AFM measurements (10 μm×10 μm,SPA400 apparatus manufactured by Seiko Instruments, Inc., probe: DFMSZDF20AL manufactured by Seiko Instruments, Inc.) confirmed that thesurface Ra value for the beads for removing blood cells of example 2 was21 nm.

Example 3

APES (grade: 4800P, number average molecular weight: 21,000) and a PAR(number average molecular weight: 25,000) were dissolved inN-methyl-2-pyrrolidone (hereafter abbreviated as NMP) to prepare apolymer solution. The weight mixing ratio between the PES, the PAR andthe NMP was set to 10.0:5.0:85.0. A mixture containing 36% of NMP inwater was prepared as a coagulant. The polymer solution was addeddropwise to the coagulant bath from a nozzle having an internal diameterof 0.25 mm and from a height approximately 10 cm above the liquidsurface within the tank. Following thorough coagulation within thecoagulant, the resulting beads were washed with distilled water,yielding beads for removing blood cells with a diameter of approximately1.5 mm. These beads for removing blood cells of example 3 weresubstantially spherical, and the proportion of the beads having a shapethat was usable as an adsorbent was 99.1% (calculated for 1,000 beads).AFM measurements (10 μm×10 μm, SPA400 apparatus manufactured by SeikoInstruments, Inc., probe: DFM SZDF20AL manufactured by SeikoInstruments, Inc.) confirmed that the surface Ra value for the beads forremoving blood cells of example 3 was 34 nm. An AFM image (10 μm×10 μm)of the beads for removing blood cells of example 3 is illustrated inFIG. 3.

Comparative Example 1

A polymer solution was prepared in the same manner as example 3. Amixture containing 70% of NMP in water was prepared as a coagulant. Thepolymer solution was added dropwise to the coagulant bath from a nozzlehaving an internal diameter of 0.25 mm and from a height approximately10 cm above the liquid surface within the tank. Following thoroughcoagulation within the coagulant, the resulting beads were washed withdistilled water, yielding beads for removing blood cells with a diameterof approximately 1.5 mm. These beads for removing blood cells ofcomparative example 1 were substantially spherical, and the proportionof the beads having a shape that was usable as an adsorbent was 72.3%(calculated for 1,000 beads). AFM measurements (10 μm×10 μm, SPA400apparatus manufactured by Seiko Instruments, Inc., probe: DFM SZDF20ALmanufactured by Seiko Instruments, Inc.) confirmed that the surface Ravalue for the beads for removing blood cells of comparative example 1was 104 nm.

Comparative Example 2

Alumina balls with a diameter of 2 mm (manufactured by As OneCorporation) were used as the beads for removing blood cells ofcomparative example 2. AFM measurements (10 μm×10 μm, SPA400 apparatusmanufactured by Seiko Instruments, Inc., probe: DFM SZDF20ALmanufactured by Seiko Instruments, Inc.) confirmed that the surface Ravalue for the beads for removing blood cells of comparative example 2was 124 nm.

Comparative Example 3

Cellulose acetate beads with a diameter of 2 mm (extracted fromAdacolumn, manufactured by JIMRO Co., Ltd.) were used as the beads forremoving blood cells of comparative example 3. AFM measurements (10μm×10 μm, SPA400 apparatus manufactured by Seiko Instruments, Inc.,probe: DFM SZDF20AL manufactured by Seiko Instruments, Inc.) confirmedthat the surface Ra value for the beads for removing blood cells ofcomparative example 3 was 133 nm. An AFM image (10 μm×10 μm) of thebeads for removing blood cells of comparative example 3 is illustratedin FIG. 4. As is evident from FIG. 4, large surface irregularities existon the surface of the beads for removing blood cells of comparativeexample 3.

[White Blood Cells—Platelets Adsorption Test]

A sample (38 mL) of each of the beads for removing blood cells fromexamples 1 to 3 and comparative examples 1 to 3 described above was usedto fill a column of diameter 27 mm and length 70 min (internal volume:40 mL). A 250 mL sample of blood from a healthy person was collected ina blood bag, and following heparinization, the blood was circulatedthrough the column for 30 minutes at a rate of 7 mL/min, and theadsorption rates for the beads for removing blood cells were calculatedfrom the changes in the number of granulocytes (neutrophils), the numberof platelets and the number of lymphocytes. The results are listed inTable 1. Examples 2 and 3, and comparative examples 1 to 3 wereconverted to modules in the same manner as that described for example 1.

TABLE 1 Granulocyte Lymphocyte Platelet Ra adsorption adsorptionadsorption Coagulation during Adsorbent (nm) Yield (%) (%) (%) and aftercirculation Example 1 Polyarylate 15 99.6 62 5 59 No coagulation beadsor blood retention Example 2 Polyethersulfone 21 99.8 55 2 48 Nocoagulation beads or blood retention Example 3 Polyarylate- 34 99.1 57 457 No coagulation Polyethersulfone or blood retention beads ComparativePolyarylate- 104 72.3 65 6 62 No coagulation example 1 Polyethersulfoneor blood retention beads Comparative Alumina balls 124 — 62 10 61Coagulation during example 2 circulation Comparative Cellulose 133 — 510 19 No coagulation example 3 acetate beads or blood retention

For the beads for removing blood cells of comparative example 1 (Ra=104nm), the yield of beads having a shape that was usable as an adsorbentdecreased significantly, which causes an increase in the productioncosts. For the beads for removing blood cells of comparative example 2(Ra=124 nm), although adsorption of white blood cells and platelets wasconfirmed, a problem occurred in that the blood coagulated duringcirculation through the column. For the beads for removing blood cellsof comparative example 3 (Ra=133 nm), the adsorption of platelets wasfound to be poor.

For the beads for removing blood cells according to examples 1 to 3, itwas found that white blood cells and platelets were able to be adsorbedefficiently, with no coagulation or retention of the blood, eitherduring or after circulation through the column.

Example 4

A polymer solution was prepared using a PAR, a PES and NMP. The mixingweight ratio between the PAR and the PES was 1:1. An NMP aqueoussolution was used as a coagulant and a core liquid. Using a doublespinneret, the polymer solution was discharged, together with the coreliquid, into the above coagulant to prepare hollow fibers for removingblood cells, and 10,000 of these hollow fibers for removing blood cellswere bundled together to form a hollow fiber bundle. As illustrated inFIG. 5, this hollow fiber bundle 200 was packed inside a cylindricalcasing 210 produced from a polycarbonate, and with a pair of polyestermeshes 220 pressed against the hollow fiber bundle, headers 230 fittedwith a blood inlet port and a blood outlet port respectively wereattached to the casing to complete the module. The meshes 220 used had amesh size that was finer than the diameter of the hollow fibers. AFMmeasurements (10 μm×10 μm, SPA400 apparatus manufactured by SeikoInstruments, Inc., probe: DFM SZDF20AL manufactured by SeikoInstruments, Inc.) confirmed that the surface Ra value for the hollowfibers for removing blood cells of example 4 was 5.2 nm.

Comparative Example 4

For comparative example 4, the filler from the granulocyte adsorptioncolumn Adacolumn (cellulose acetate beads with a diameter ofapproximately 2 mm) was used. AFM measurements (10 μm×10 μm, SPA400apparatus manufactured by Seiko Instruments, Inc., probe: DFM SZDF20ALmanufactured by Seiko Instruments, Inc.) confirmed that the surface Ravalue for the beads of comparative example 4 was 133 nm.

[White Blood Cells—Platelets Adsorption Test]

Samples equivalent to a surface area of 3,260 cm² of the hollow fibersfor removing blood cells of example 4 and the beads of comparativeexample 4 were each used to fill a column of diameter 27 mm and length70 mm (internal volume: 40 mL). A 250 mL sample of blood from a healthyperson was collected in a blood bag, and following heparinization, theblood was circulated through the column for 30 minutes at a rate of 7mL/min, and the adsorption rates for the module were calculated from thechanges in the number of granulocytes (neutrophils), the number ofplatelets and the number of lymphocytes. The results are listed in Table2.

TABLE 2 Adsorption rate (n = 6) Granulocytes (neutrophils) PlateletsLymphocytes Example 4 67% 78% 0% Comparative 57% 19% 0% example 4

As is evident from Table 2, when the hollow fibers for removing bloodcells of example 4 were used, it was confirmed that both thegranulocytes and platelets were removed efficiently. In contrast, whenthe beads of comparative example 4 were used, the removal of theplatelets was inadequate.

Example 5

A polymer stock solution was prepared using a polyarylate resin(hereafter abbreviated as “PAR”, number average molecular weight:25,000, product name: U polymer, manufactured by Unitika Ltd.), apolyethersulfone resin (hereafter abbreviated as “PES”, grade: 4800P,number average molecular weight: 21,000, product name: Sumikaexcel PES,manufactured by Sumitomo Chemical Co., Ltd.) and N-methylpyrrolidone(NMP). The weight mixing ratio between the PAR, the PES and the NMP wasset to 7.5:7.5:85.0. An aqueous solution of N-methylpyrrolidone (amixture containing 60% of NMP in water) was used as a coagulant and acore liquid. Using a double spinneret, the above polymer stock solutionwas discharged, together with the core liquid, into the coagulant toprepare a hollow fiber membrane, and this membrane was cut in acontinuous manner, yielding an adsorbent for removing blood cellscomposed of short hollow fibers with an external diameter of 0.3 mm, aninternal diameter of 0.2 mm and a length of 5 mm. Although there are noparticular limitations on the technique employed for cutting the hollowfiber membrane into short fibers, from an industrial viewpoint, aconventional cutting apparatus using a cutter roller (for example, seeJP 05-96033 U, JP 09-277190 A and JP 06-27092 U) is ideal.

Measurement of the surface roughness of the adsorbent for removing bloodcells according to this example using an AFM (10 μm×10 μm, SPA400apparatus manufactured by Seiko Instruments, Inc., probe: DFM SZDF20ALmanufactured by Seiko Instruments, Inc.) yielded a result of Ra=6.2 nm.Further, the average pore diameter was 25.4 nm. The average porediameter was measured using a porosimeter (PoreMaster-60) manufacturedby Yuasa Ionics Inc.

A white blood cells and platelets adsorption test was performed bypacking a quantity of the short fibers equivalent to a total externalsurface area of approximately 0.1 m² into a polycarbonate casing(column) with an internal diameter of 27 mm and a length of 70 mm. Theratio of the length of the adsorbent for removing blood cells relativeto the internal diameter of the casing was 5 mm/27 mm×100=18.5%. Thefilling rate of the adsorbent for removing blood cells relative to thevolume of the casing was 48%.

A 250 mL sample of blood from a healthy person was collected in a bloodbag, and following heparinization, the blood was circulated through thecolumn for 30 minutes at a rate of 7 mL/min, and the adsorption ratesfor the adsorbent for removing blood cells according to example 5 werecalculated from the changes in the number of granulocytes (neutrophils),the number of platelets and the number of lymphocytes. The resultsrevealed adsorption rates for the granulocytes, platelets andlymphocytes of 54%, 61% and 2% respectively.

The adsorbent for removing blood cells according to example 5 exhibiteda satisfactory adsorption capacity for the granulocytes and plateletsthat function as inflammatory cells, but a low adsorption capacity forthe lymphocytes, which function as memory cells and are preferablyretained within the body. Furthermore, air removal during priming wassimple, and no coagulation of the blood was observed.

Example 6

A hollow fiber membrane was prepared using the same method as thatdescribed for example 5, and the resulting hollow fiber membrane was cutto lengths of 10 mm (external diameter: 0.3 mm, internal diameter: 0.2mm), yielding an adsorbent for removing blood cells composed of shorthollow fibers. The ratio of the length of the adsorbent for removingblood cells relative to the internal diameter of the casing was 10 mm/27mm×100=37.0%. The filling rate of the adsorbent for removing blood cellsrelative to the volume of the casing was 36%.

The adsorbent for removing blood cells according to example 6 wassubjected to the same blood cells adsorption test as that describedabove for example 5. The test results revealed adsorption rates for thegranulocytes, platelets and lymphocytes of 55%, 58% and 3% respectively.

The adsorbent for removing blood cells according to example 6 exhibiteda satisfactory adsorption capacity for the granulocytes and plateletsthat function as inflammatory cells, but a low adsorption capacity forthe lymphocytes, which function as memory cells and are preferablyretained within the body. Furthermore, air removal during priming wassimple, and no coagulation of the blood was observed.

Example 7

A hollow fiber membrane was prepared using the same method as thatdescribed for example 5, and the resulting hollow fiber membrane was cutto lengths of 15 mm (external diameter: 0.3 mm, internal diameter: 0.2mm), yielding an adsorbent for removing blood cells composed of shorthollow fibers. The ratio of the length of the adsorbent for removingblood cells relative to the internal diameter of the casing was 15 mm/27mm×100=55.6%. The filling rate of the adsorbent for removing blood cellsrelative to the volume of the casing was 21%.

The adsorbent for removing blood cells according to example 7 wassubjected to the same blood cells adsorption test as that describedabove for example 5. The test results revealed adsorption rates for thegranulocytes, platelets and lymphocytes of 51%, 55% and 3% respectively.

The adsorbent for removing blood cells according to example 7 exhibiteda satisfactory adsorption capacity for the granulocytes and plateletsthat function as inflammatory cells, but a low adsorption capacity forthe lymphocytes, which function as memory cells and are preferablyretained within the body. Furthermore, air removal during priming wassimple, and no coagulation of the blood was observed.

Comparative Example 5

A hollow fiber membrane was prepared using the same method as thatdescribed for example 5, and the resulting hollow fiber membrane was cutto lengths of 20 mm (external diameter: 0.3 mm, internal diameter: 0.2mm), yielding an adsorbent for removing blood cells composed of shorthollow fibers. The ratio of the length of the adsorbent for removingblood cells relative to the internal diameter of the casing was 20 mm/27mm×100=74.1%. The filling rate of the adsorbent for removing blood cellsrelative to the volume of the casing was 15%.

The adsorbent for removing blood cells according to comparative example5 was subjected to the same blood cells adsorption test as thatdescribed above for example 5. The test results revealed adsorptionrates for the granulocytes, platelets and lymphocytes of 53%, 57% and 2%respectively.

The adsorbent for removing blood cells according to comparative example5 exhibited a satisfactory adsorption capacity for the granulocytes andplatelets that function as inflammatory cells, but a low adsorptioncapacity for the lymphocytes, which function as memory cells and arepreferably retained within the body. However, because movement of thefibers inside the casing was restricted, air bubbles tended to betrapped by the fibers, making air removal during priming difficult, andby the completion of the blood circulation process, blood coagulationwas visible on the adsorbent for removing blood cells.

Example 8

A polymer stock solution was prepared using a PAR (number averagemolecular weight: 25,000, product name: U polymer, manufactured byUnitika Ltd.) and NMP. The weight mixing ratio between the PAR and theNMP was set to 15:85. An aqueous solution of N-methylpyrrolidone (amixture containing 60% of NMP in water) was used as a coagulant. Using aspinneret, the above polymer stock solution was discharged into thecoagulant to prepare a solid fiber, and this film was cut in acontinuous manner, yielding an adsorbent for removing blood cellscomposed of short solid fibers with an external diameter of 0.25 mm anda length of 5 mm. The ratio of the length of the adsorbent for removingblood cells relative to the internal diameter of the casing was 5 mm/27mm×100=18.5%. The filling rate of the adsorbent for removing blood cellsrelative to the volume of the casing was 42%.

Measurement of the surface roughness of the adsorbent for removing bloodcells according to this example using an AFM (10 μm×10 μm, SPA400apparatus manufactured by Seiko Instruments, Inc., probe: DFM SZDF20ALmanufactured by Seiko Instruments, Inc.) yielded a result of Ra=3.4 nm.Further, the average pore diameter was 16.7 nm. The average porediameter was measured using a porosimeter (PoreMaster-60) manufacturedby Yuasa Ionics Inc.

The adsorbent for removing blood cells according to example 8 wassubjected to the same blood cells adsorption test as that describedabove for example 5. The test results revealed adsorption rates for thegranulocytes, platelets and lymphocytes of 65%, 62% and 6% respectively.

The adsorbent for removing blood cells according to example 8 exhibiteda satisfactory adsorption capacity for the granulocytes and plateletsthat function as inflammatory cells, but a low adsorption capacity forthe lymphocytes, which function as memory cells and are preferablyretained within the body. Furthermore, air removal during priming wassimple, and no coagulation of the blood was observed.

Example 9

A solid fiber was prepared using the same method as that described forexample 8, and the resulting solid fiber was cut to lengths of 10 mm(external diameter: 0.25 mm), yielding an adsorbent for removing bloodcells composed of short solid fibers. The ratio of the length of theadsorbent for removing blood cells relative to the internal diameter ofthe casing was 10 mm/27 mm×100=37.0%. The filling rate of the adsorbentfor removing blood cells relative to the volume of the casing was 31%.

The adsorbent for removing blood cells according to example 9 wassubjected to the same blood cells adsorption test as that describedabove for example 5. The test results revealed adsorption rates for thegranulocytes, platelets and lymphocytes of 66%, 60% and 7% respectively.

The adsorbent for removing blood cells according to example 9 exhibiteda satisfactory adsorption capacity for the granulocytes and plateletsthat function as inflammatory cells, but a low adsorption capacity forthe lymphocytes, which function as memory cells and are preferablyretained within the body. Furthermore, air removal during priming wassimple, and no coagulation of the blood was observed.

Example 10

A solid fiber was prepared using the same method as that described forexample 8, and the resulting solid fiber was cut to lengths of 15 mm(external diameter: 0.25 mm), yielding an adsorbent for removing bloodcells composed of short solid fibers. The ratio of the length of theadsorbent for removing blood cells relative to the internal diameter ofthe casing was 15 mm/27 mm×100=55.6%. The filling rate of the adsorbentfor removing blood cells relative to the volume of the casing was 20%.

The adsorbent for removing blood cells according to example 10 wassubjected to the same blood cells adsorption test as that describedabove for example 5. The test results revealed adsorption rates for thegranulocytes, platelets and lymphocytes of 64%, 58% and 5% respectively.

The adsorbent for removing blood cells according to example 10 exhibiteda satisfactory adsorption capacity for the granulocytes and plateletsthat function as inflammatory cells, but a low adsorption capacity forthe lymphocytes, which function as memory cells and are preferablyretained within the body. Furthermore, air removal during priming wassimple, and no coagulation of the blood was observed.

Example 11

A polymer stock solution was prepared using a PES (grade: 4800P, numberaverage molecular weight: 21,000, product name: Sumikaexcel PES,manufactured by Sumitomo Chemical Co., Ltd.) and NMP. The weight mixingratio between the PES and the NMP was set to 15:85. An aqueous solutionof N-methylpyrrolidone (a mixture containing 60% of NMP in water) wasused as a coagulant. Using a spinneret, the above polymer stock solutionwas discharged into the coagulant to prepare a solid fiber, and thisfilm was cut in a continuous manner, yielding an adsorbent for removingblood cells composed of short solid fibers with an external diameter of0.25 mm and a length of 10 mm. The ratio of the length of the adsorbentfor removing blood cells relative to the internal diameter of the casingwas 10 mm/27 mm×100=37%. The filling rate of the adsorbent for removingblood cells relative to the volume of the casing was 28%.

Measurement of the surface roughness of the adsorbent for removing bloodcells according to this example using an AFM (10 μm×10 μm, SPA400apparatus manufactured by Seiko Instruments, Inc., probe: DFM SZDF20ALmanufactured by Seiko Instruments, Inc.) yielded a result of Ra=5.2 nm.Further, the average pore diameter was 12.4 nm. The average porediameter was measured using a porosimeter (PoreMaster-60) manufacturedby Yuasa Ionics Inc.

The adsorbent for removing blood cells according to example 11 wassubjected to the same blood cells adsorption test as that describedabove for example 5. The test results revealed adsorption rates for thegranulocytes, platelets and lymphocytes of 53%, 48% and 0% respectively.

The adsorbent for removing blood cells according to example 11 exhibiteda satisfactory adsorption capacity for the granulocytes and plateletsthat function as inflammatory cells, but a low adsorption capacity forthe lymphocytes, which function as memory cells and are preferablyretained within the body. Furthermore, air removal during priming wassimple, and no coagulation of the blood was observed.

Example 12

A hollow fiber membrane (internal diameter: 200 μm, external diameter:230 μm) was extracted from a dialyzer FB-150F manufactured by NiproCorporation that used the cellulose acetate hollow fiber membrane, andthe film was cut into 10 mm lengths, yielding an adsorbent for removingblood cells composed of short hollow fibers. The filling rate of theadsorbent for removing blood cells relative to the volume of the casingwas 31%.

The adsorbent for removing blood cells according to example 12 wassubjected to the same blood cells adsorption test as that describedabove for example 5. The test results revealed adsorption rates for thegranulocytes, platelets and lymphocytes of 55%, 15% and 1% respectively.

The adsorbent for removing blood cells according to example 12 exhibiteda satisfactory adsorption capacity for the granulocytes that function asinflammatory cells. In contrast, the adsorption capacity for theplatelets and lymphocytes was low. Air removal during priming wassimple, and no coagulation of the blood was observed.

Table 3 below summarizes various information and the results of theblood cells adsorption tests for the adsorbents for removing blood cellsof examples 5 to 12 and comparative example 5.

TABLE 3 Ratio with Filling rate Absorbent for Fiber internal GranulocyteLymphocyte Platelet of absorbent removing length diameter of absorptionabsorption absorption State of air removal for removing blood cells (mm)casing (%) (%) (%) (%) and blood coagulation blood cells (%) Example 5Polyarylate 5 18.5 54 2 61 Good air removal, no 48 Polyethersulfoneblood coagulation hollow fibers Example 6 Polyarylate 10 37.0 55 3 58Good air removal, no 36 Polyethersulfone blood coagulation hollow fibersExample 7 Polyarylate 15 55.6 51 3 55 Good air removal, no 21Polyethersulfone blood coagulation hollow fibers Comparative Polyarylate20 74.1 53 2 57 Good air removal, some 15 example 5 Polyethersulfoneblood coagulation hollow fibers Example 8 Polyarylate 5 18.5 65 6 62Good air removal, no 42 solid fibers blood coagulation Example 9Polyarylate 10 37.0 66 7 60 Good air removal, no 31 solid fibers bloodcoagulation Example 10 Polyarylate 15 55.6 64 5 58 Good air removal, no20 solid fibers blood coagulation Example 11 Polyethersulfone 10 37.0 530 48 Good air removal, no 28 solid fibers blood coagulation Example 12Cellulose 10 37.0 55 1 15 Good air removal, no 31 triacetate bloodcoagulation hollow fibers

Example 13

A polymer stock solution was prepared using a polyarylate resin(hereafter abbreviated as “PAR”, number average molecular weight:25,000, product name: U polymer, manufactured by Unitika Ltd.), apolyethersulfone resin (hereafter abbreviated as “PES”, grade: 4800P,number average molecular weight: 21,000, product name: Sumikaexcel PES,manufactured by Sumitomo Chemical Co., Ltd.) and N-methylpyrrolidone(NMP). The weight mixing ratio between the PAR, the PES and the NMP wasset to 7.5:7.5:85.0. An aqueous solution of N-methylpyrrolidone (amixture containing 60% of NMP in water) was used as a coagulant and acore liquid. Using a double spinneret, the above polymer stock solutionwas discharged, together with the core liquid, into the coagulant toprepare a hollow fiber membrane, and this film was cut in a continuousmanner, yielding an adsorbent for removing blood cells composed of shorthollow fibers with an external diameter of 300 μm, an internal diameterof 200 μm and a length of 70 mm.

Measurement of the surface roughness of the adsorbent for removing bloodcells according to this example using an AFM (10 μm×10 μm, SPA400apparatus manufactured by Seiko Instruments, Inc., probe: DFM SZDF20ALmanufactured by Seiko Instruments, Inc.) yielded a result of Ra=5.2 nm.Further, the average pore diameter was 25.4 nm.

Approximately 3,500 strands of the hollow fibers of the adsorbent forremoving blood cells according to this example (external diameter: 300μm, length 70 mm) were aligned on a flat surface, a polyester resin mesh(70 mesh, thread diameter: 71 μm) that functioned as a mesh-like fabricwas overlaid on top of the hollow fibers, and a heat sealer was thenused to fuse both ends of the adsorbent for removing blood cells to themesh, thereby sealing the end faces of the adsorbent for removing bloodcells (total adsorption surface area: approximately 2,300 cm²).Subsequently, the end portions on the outside of the fused portions werecut off and discarded, and the mesh-like fabric was rolled along thedirection of alignment of the adsorbent for removing blood cells, thusforming a cylindrical adsorbent for removing blood cells composed of abundle of the fibers of the adsorbent for removing blood cells with themesh-like fabric interposed therebetween as a spacer.

As illustrated in FIG. 8, the obtained cylindrical adsorbent 350 forremoving blood cells was packed inside a casing 20 produced from apolycarbonate (total length: 70 mm, internal diameter: 27 mm, volume: 40mL), and a pair of headers 40 a and 40 b fitted with a blood inlet and ablood outlet respectively were attached to the casing to completepreparation of a blood cells removal module A.

Comparative Example 6

The filler from the granulocyte adsorption column Adacolumn(manufactured by JIMRO Co., Ltd.) (cellulose acetate beads with adiameter of approximately 2 mm, Ra=133 nm) was packed inside apolycarbonate casing of the same type as that used in example 13 (totallength: 70 mm, internal diameter: 27 mm, volume: 40 mL), and a pair ofheaders fitted with a blood inlet and a blood outlet respectively wereattached to the casing to complete preparation of a blood cells removalmodule B.

[Method of Evaluation]

A 500 mL sample of blood was collected from a healthy person, andfollowing heparinization, the blood was divided into two blood bags of250 mL, one sample was circulated through each of the two modules for 30minutes at a rate of 7 mL/min, and the adsorption rates for each bloodcells removal module were calculated from the changes in the number ofgranulocytes (neutrophils), the number of platelets and the number oflymphocytes. The results are listed below in Table 4. These resultsrepresent the average values for the results of 6 separate measurements.

TABLE 4 Adsorption rate (%) Granulocytes (neutrophils) PlateletsLymphocytes Example 67 78 0 13 Comparative 57 19 0 example 6

From the results in Table 4 it is evident that the blood cells removalmodule A of example 13 exhibited a platelet adsorption rate that was farsuperior to that of the blood cells removal module B of comparativeexample 6.

Example 14

Approximately 8,000 strands of the hollow fibers of the adsorbent forremoving blood cells obtained in example 13 (external diameter: 300 μm,length 70 mm) were aligned on a flat surface, a polyester resin mesh (70mesh, thread diameter: 100 μm) that functioned as a mesh-like fabric wasoverlaid on top of the hollow fibers, and a heat sealer was then used tofuse both ends of the adsorbent for removing blood cells to the mesh,thereby sealing the end faces of the adsorbent for removing blood cells(total adsorption surface area: approximately 0.9 m²). Subsequently, theend portions on the outside of the fused portions were cut off anddiscarded, and the mesh-like fabric was rolled along the direction ofalignment of the adsorbent for removing blood cells, thus forming acylindrical adsorbent for removing blood cells composed of a bundle ofthe fibers of the adsorbent for removing blood cells with the mesh-likefabric interposed therebetween as a spacer.

As illustrated in FIG. 8, the obtained cylindrical adsorbent 350 forremoving blood cells was packed inside a polycarbonate casing 20 (totallength: 185 mm, internal diameter: 59 mm, volume: 324 mL), and a pair ofheaders 40 a and 40 b fitted with a blood inlet and a blood outletrespectively were attached to the casing to complete preparation of ablood cells removal module C.

REFERENCE EXAMPLE

A polymer stock solution was prepared using a polyarylate resin(hereafter abbreviated as “PAR”, number average molecular weight:25,000, product name: U polymer, manufactured by Unitika Ltd.), apolyethersulfone resin (hereafter abbreviated as “PES”, grade: 4800P,number average molecular weight: 21,000, product name: Sumikaexcel PES,manufactured by Sumitomo Chemical Co, Ltd.) and N-methylpyrrolidone(NMP). The weight mixing ratio between the PAR, the PES and the NMP wasset to 7.5:7.5:85.0. An aqueous solution of N-methylpyrrolidone (amixture containing 60% of NMP in water) was used as a coagulant. Thepolymer solution was added dropwise to the coagulant bath from a nozzlehaving an internal diameter of 0.25 mm and from a height approximately20 cm above the liquid surface within the tank. Following thoroughcoagulation within the coagulant, the resulting beads were washed withdistilled water, yielding beads for removing blood cells with a diameterof approximately 1 mm.

Approximately 300,000 of the beads for removing blood cells obtained inthis reference example (approximately 290 mL) (adsorption surface area:approximately 0.9 m²) were packed in a polycarbonate casing (totallength: 185 mm, internal diameter: 59 mm, volume: 324 mL), and a pair ofheaders 40 a and 40 b fitted with a blood inlet and a blood outletrespectively were attached to the casing to complete preparation of ablood cells removal module D.

[Method of Evaluation]

3 L of heparinized bovine blood (hematocrit value: 32%) was circulatedthrough each of the blood cells removal modules at a rate of 50 mL/min,and after 20 minutes, the inlet pressure at the blood inlet of the bloodcells removal module and the outlet pressure at the blood outlet weremeasured, and the pressure loss within the module was calculated. Theresults are listed below in Table 5.

TABLE 5 Module inlet Module outlet Pressure loss pressure (Pa) pressure(Pa) (Pa) Reference 6,000 3,866 2,133 Example Example 4,666 4,000 666 14

From the results in Table 5 it is evident that the blood cells removalmodule C of example 14 had a smaller pressure loss than that of theblood cells removal module D that was filled with the beads of thereference example. The granulocyte (neutrophil) and platelet adsorptionrates for the blood cells removal module C of example 14 weresubstantially the same as those for the blood cells removal module Dfilled with the beads of the reference example.

[Addendum]

Another preferred embodiment of the present invention is describedbelow.

A blood cells removal module according to an embodiment of the presentinvention comprises a casing provided with an inlet for introducing ablood flow prior to blood cells removal and an outlet for dischargingthe blood flow following blood cells removal, an adsorbent for removingblood cells composed of short fibers that is housed inside the casing,and meshes that are provided on the inside of the inlet and outletrespectively and retain the adsorbent for removing blood cells withinthe casing, wherein the length of the adsorbent for removing blood cellsis within a range from 1 to 60% of the internal diameter of the casing.

According to this embodiment, white blood cells and platelets can beremoved efficiently while problems such as air removal prior to use andin-circuit coagulation during blood flow are suppressed. The length ofthe adsorbent for removing blood cells is preferably within a range from18 to 56% of the internal diameter of the casing. This enables the aboveeffects to be further enhanced.

In the above embodiment, the filling rate of the adsorbent for removingblood cells relative to the volume of the casing may be within a rangefrom 20 to 60%.

Further, in the above embodiment, the adsorbent for removing blood cellsmay be composed of hollow fibers or solid fibers. In those cases wherethe adsorbent for removing blood cells is composed of hollow fibers, theamount of material used can be reduced compared with those cases wheresolid fibers are used. Furthermore, hollow fibers also offer theadvantage that blood cell adsorption on the internal surfaces of thefibers can also be expected.

Furthermore, in the above embodiment, the adsorbent for removing bloodcells may be formed from a hydrophobic polymer resin. In this case, thehydrophobic polymer resin may be a polyarylate resin having a repeatingunit represented by chemical formula (1) shown below.

Furthermore, the hydrophobic polymer resin may comprise apolyethersulfone resin having a repeating unit represented by chemicalformula (2) or chemical formula (3) shown below.

In chemical formula (2), each of R3 and R4 represents a lower alkylgroup of 1 to 5 carbon atoms, and R3 and R4 may be the same ordifferent.

In the above embodiment, the hydrophobic polymer resin may include apolyarylate resin having a repeating unit represented by chemicalformula (1) shown above, and a polyethersulfone resin having a repeatingunit represented by chemical formula (2) or chemical formula (3) shownabove.

The blood cells removal module of the above embodiment may be used forremoving white blood cells and platelets from blood.

Moreover, appropriate combinations of each of the elements describedabove are also deemed to be included within the scope of the inventionfor which patent protection is sought on the basis of the presentdescription.

Furthermore, other preferred embodiments of the present invention aredescribed below.

(I) A blood cells removal module comprising a casing provided with aninlet for introducing a blood flow prior to blood cells removal and anoutlet for discharging the blood flow following blood cells removal, anda cylindrical adsorbent for removing blood cells, which is formed byrolling an integrated blood cells removal adsorbent-containing mesh-likefabric, in which an adsorbent for removing blood cells that is formedfrom a plurality of aligned hollow fibers or solid fibers is secured atboth ends to a mesh-like fabric that is permeable to blood, along thedirection of alignment of the adsorbent for removing blood cells.

(II) The blood cells removal module according to (I) above, furthercomprising meshes which are provided on the inside of the inlet andoutlet respectively, and retain the adsorbent for removing blood cellswithin the casing.

(III) The blood cells removal module according to (I) or (II) above,wherein the adsorbent for removing blood cells comprises at leasthydrophobic polymer resin selected from amongst polyarylate resinshaving a repeating unit represented by chemical formula (1) shown below,and polyethersulfone resins having a repeating unit represented bychemical formula (2) or chemical formula (3) shown below.

In chemical formula (1), each of R1 and R2 represents a lower alkylgroup of 1 to 5 carbon atoms, and R1 and R2 may be the same ordifferent.

In chemical formula (2), each of R3 and R4 represents a lower alkylgroup of 1 to 5 carbon atoms, and R3 and R4 may be the same ordifferent.

(IV) The blood cells removal module according to any one of (I) to (III)above, which is used for removing white blood cells and platelets fromblood.

(V) A method of producing a blood cells removal module, the methodcomprising: forming an integrated blood cells removaladsorbent-containing mesh-like fabric by securing both ends of anadsorbent for removing blood cells that is formed from a plurality ofaligned hollow fibers or solid fibers to a mesh-like fabric that ispermeable to blood, forming a cylindrical adsorbent for removing bloodcells by rolling the integrated blood cells removal adsorbent-containingmesh-like fabric along the direction of alignment of the adsorbent forremoving blood cells, and housing the cylindrical adsorbent for removingblood cells inside a casing provided with an inlet for introducing ablood flow prior to blood cells removal and an outlet for dischargingthe blood flow following blood cells removal.

(VI) The method of producing a blood cells removal module according to(V) above, wherein when forming the integrated blood cells removaladsorbent-containing mesh-like fabric, the adsorbent for removing bloodcells is composed of hollow fibers, and in those cases where both endsof the adsorbent for removing blood cells are secured by thermal fusionto the mesh-like fabric that is permeable to blood, the hollows aresealed at both ends of the thermally fused adsorbent for removing bloodcells.

According to the embodiment described above, the pressure loss duringblood cells removal can be reduced compared with the case of anadsorbent for removing blood cells composed of beads.

Further, the mesh-like fabric functions as a spacer for the adsorbentfor removing blood cells formed from the plurality of hollow fibers orsolid fibers, meaning the distance between individual fibers of theadsorbent for removing blood cells is substantially uniform throughoutthe blood cells removal module and is formed with an appropriatespacing. Accordingly, stagnation of the blood flow through the bloodcells removal module is suppressed. As a result, the blood cellsadsorption efficiency improves, and because unlike conventionaladsorbents, the ends of the adsorbent for removing blood cells composedof fibers need not necessarily be secured using a mesh, the number ofcomponents can be reduced and the production process can be simplified.

Furthermore, in those cases where the adsorbent for removing blood cellsis composed of hollow fibers, because the hollows at both end faces ofthe thermally fused adsorbent for removing blood cells are sealed,penetration of the blood into the interior of the hollow fibers of theadsorbent for removing blood cells during blood cells removal can besuppressed, thereby preventing blood retention.

Although the present invention has been described above in detail, thescope of the present invention is not limited by the precedingdescription.

Furthermore, the detailed description of the invention, the claims, thedrawings and the abstract of each of the specifications disclosed inJapanese Patent Application No. 2008-109381 filed on Apr. 18, 2008,Japanese Patent Application No. 2008-154418 filed on Jun. 12, 2008,Japanese Patent Application No. 2008-299521 filed on Nov. 25, 2008, andJapanese Patent Application No. 2009-098289 filed on Apr. 14, 2009 areincorporated within this application.

INDUSTRIAL APPLICABILITY

The present invention is ideal for applications for the removal of bloodcells.

Reference Numerals

-   1, 10, 300: Blood cells removal module-   20: Casing-   21: Casing main body-   22, 24: Blood flow inlet and outlet-   30 a, 30 b: Mesh-   40 a, 40 b: Header-   350, 350 a: Cylindrical adsorbent for removing blood cells-   52: Mesh-like fabric-   54: Adsorbent for removing blood cells-   56: Fused portion-   60: Integrated blood cells removal adsorbent-containing mesh-like    fabric-   70: Fusion device-   100: Blood cells removal beads production apparatus-   110: Stock solution tank-   120: Pump-   130: Nozzle-   140: Coagulant bath-   144: Coagulant collection tank-   150: Beads for removing blood cells

The invention claimed is:
 1. An adsorbent for removing blood cells, usedfor removing white blood cells and platelets from blood, which is formedfrom a hydrophobic polymer resin, and has a surface center line averageroughness of 5 to 100 nm, and wherein the hydrophobic polymer resin is apolyarylate resin having a repeating unit represented by chemicalformula (1) shown below, and the number average molecular weight of thepolyarylate resin is within a range from 20,000 to 30,000:

wherein each of R1 and R2 represents a lower alkyl group of 1 to 5carbon atoms, and R1 and R2 may be identical or different.
 2. Theadsorbent for removing blood cells according to claim 1, wherein thehydrophobic polymer resin further comprises a polyethersulfone resinhaving a repeating unit represented by chemical formula (2) or chemicalformula (3) shown below:

wherein each of R3 and R4 represents a lower alkyl group of 1 to 5carbon atoms, and R3 and R4 may be identical or different


3. The adsorbent for removing blood cells according to claim 2, whereinthe number average molecular weight of the polyethersulfone resin iswithin a range from 15,000 to 30,000.
 4. The adsorbent for removingblood cells according to claim 1, wherein the adsorbent has a surfacecenter line average roughness of 5 to 34 nm.
 5. The adsorbent forremoving blood cells according to claim 1, wherein the adsorbent is in abeads form.
 6. The adsorbent for removing blood cells according to claim1, wherein the adsorbent is in a form of hollow fibers or solid fibers.